The finding that schizophrenia (SZ) is a disorder characterized by a decrease of reelin and GAD67 (Guidotti et al., 2000), an increase of DNMT1 mRNA expression in cortical GABAergic interneurons (Costa et al., 2002a), and a hypermethylation of the reelin promoter CpG islands (Grayson, personal communication) encouraged us to consider that hypermethylation of promoter CpG islands is a mechanism operative in the dysfunction of GABAergic neurons in SZ. This project's overarching objective is to develop animal models of epigenetic reelin and GAD67 expression downregulation. We hypothesize that the downregulation of reelin and GAD67 in cortical GABAergic neurons of SZ brains can be replicated in mouse telencephalic GABAergic neurons with protracted administration of L-methionine in doses that increase: i) the content of the methyl donor S-adenosyl-methionine; ii) DNA-(cytosine-5)-methyltransferase (DNMT1) activity; and iii) covalent cytosine residues methylated in position 5 on the CpG-rich promoter regions of reelin and GADe? genes. One of the regulatory mechanisms involved in the process of control of gene activity by DNMT1 is its accessibility to target DNA segments. This accessibility may be regulated by the acetylated or deacetylated status of the nucleosomal core histones, which is governed by the balance of the activities of histone acetyltransferases (HAT) and histone deacetylases (HDAC). Studies in the field of cancer suggest that the increased activity of DNMTs observed in tumor cells can be downregulated by reducing HDAC activities with specific inhibitors. Hence, we have focused our attention on the action of HDAC inhibitors (i.e., valproate and benzamides) as putative drugs that may, by increasing core histone tail acetylation at nucleosomal sites, normalize in nuclei of telencephalic GABAergic neurons-reelin and GAD67 expression downregulation induced by hypermethylation of reelin or GAD67 promoter CpG islands. Recent reports suggest that typical and atypical antipsychotics are more potent, more efficacious, and less toxic if they are co-administered with valproate (VPA). The beneficial effects in the treatment of SZ obtained with the weak HDAC inhibitor VPA suggest that more potent HDAC inhibitors may represent a new opportunity for pharmacological interventions of putative therapeutic value in mitigating vulnerability to SZ among high risk individuals.